Commonly used anesthetics cause widespread neurodegeneration in the developing mammalian brain. Neurotoxicity occurs due to caspase activation via the mitochondrial pathway of apoptosis followed by activation of death receptor and neurotrophic-factor activated pathways. Carbon monoxide (CO) has anti- apoptotic properties and exhaled endogenous CO is commonly re-breathed during low-flow anesthesia (LFA) in infants and children resulting in sub-clinical CO exposure. There is a major gap in our knowledge because it is unknown if CO exposure inhibits anesthesia-induced neuroapoptosis. The specific hypothesis behind this proposal is that low concentrations of inspired CO prevent anesthesia-induced neurotoxicity. The experiments outlined in this proposal are aimed to determine the mechanism of CO-mediated inhibition of isoflurane-induced neuroapoptosis, to identify the neurologic consequences of simultaneous CO and isoflurane exposure in newborn mice, and to develop a large animal model of CO re-breathing during LFA. This proposal will lay the groundwork for development of CO re-breathing during LFA as a preventative intervention designed to protect against anesthesia-induced neurodegeneration.